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Transactivation of Vascular Endothelial Growth Factor (VEGF) Receptor Flk-1/KDR Is Involved in Sphingosine 1-Phosphate-stimulated Phosphorylation of Akt and Endothelial Nitric-oxide Synthase (eNOS)
- Source :
- Journal of Biological Chemistry. 277:42997-43001
- Publication Year :
- 2002
- Publisher :
- Elsevier BV, 2002.
-
Abstract
- Sphingosine 1-phosphate (S1P) and vascular endothelial growth factor (VEGF) elicit numerous biological responses including cell survival, growth, migration, and differentiation in endothelial cells mediated by the endothelial differentiation gene, a family of G-protein-coupled receptors, and fetal liver kinase-1/kinase-insert domain-containing receptor (Flk-1/KDR), one of VEGF receptors, respectively. Recently, it was reported that S1P or VEGF treatment of endothelial cells leads to phosphorylation at Ser-1179 in bovine endothelial nitric oxide synthase (eNOS), and this phosphorylation is critical for eNOS activation. S1P stimulation of eNOS phosphorylation was shown to involve G(i) protein, phosphoinositide 3-kinase, and Akt. VEGF also activates eNOS through Flk-1/KDR, phosphoinositide 3-kinase, and Akt, which suggested that S1P and VEGF may share upstream signaling mediators. We now report that S1P treatment of bovine aortic endothelial cells acutely increases the tyrosine phosphorylation of Flk-1/KDR, similar to VEGF treatment. S1P-mediated phosphorylation of Flk-1/KDR, Akt, and eNOS were all inhibited by VEGF receptor tyrosine kinase inhibitors and by antisense Flk-1/KDR oligonucleotides. Our study suggests that S1P activation of eNOS involves G(i), calcium, and Src family kinase-dependent transactivation of Flk-1/KDR. These data are the first to establish a critical role of Flk-1/KDR in S1P-stimulated eNOS phosphorylation and activation.
- Subjects :
- Transcriptional Activation
Vascular Endothelial Growth Factor A
Nitric Oxide Synthase Type III
Cell Survival
Endothelial Growth Factors
Protein Serine-Threonine Kinases
Biochemistry
Oligodeoxyribonucleotides, Antisense
Phosphatidylinositol 3-Kinases
chemistry.chemical_compound
GTP-Binding Proteins
Sphingosine
Enos
Proto-Oncogene Proteins
Animals
Phosphorylation
Molecular Biology
Aorta
Cells, Cultured
Lymphokines
Base Sequence
biology
Vascular Endothelial Growth Factors
Chemistry
Kinase insert domain receptor
Tyrosine phosphorylation
Cell Biology
biology.organism_classification
Vascular Endothelial Growth Factor Receptor-2
Cell biology
Enzyme Activation
Vascular endothelial growth factor B
Vascular endothelial growth factor
Kinetics
Vascular endothelial growth factor A
cardiovascular system
Cancer research
Intercellular Signaling Peptides and Proteins
Cattle
Endothelium, Vascular
Lysophospholipids
Nitric Oxide Synthase
Proto-Oncogene Proteins c-akt
Tyrosine kinase
Cell Division
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 277
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....68f48d5c05511e2eab48a86cf359bd48